Phenothiazines are a subgroup of thiazines. They are primarily used as neuroleptics.

What are phenothiazines?

Phenothiazines are derivatives of phenothiazine which are of pharmacological relevance. In medicine, they are used as neuroleptics. There they are also known as tricyclic neuroleptics.

The history of phenothiazines can be traced back to the beginning of organic chemistry. In 1865, the German chemist August Kekule (1829-1896) presented the thesis that carbon atoms are located within organic substances in ring systems. This was initially important for the paint industry, which produced from 1876 the dyes thionin and methylene blue. Both had a phenothiazine structure. Later, medicine attempted to treat disorders such as depression, headaches, and malaria with methylene blue, but this was ultimately unsuccessful.

At the beginning of the 20th century, the phenothiazines seemed to be forgotten and were used primarily in veterinary medicine for the treatment of worm diseases. In humans, however, therapies due to excessive toxicity have not been considered. From the 1940s on, however, medical research began to focus more on phenothiazines. The French pharmaceutical company Rhone-Poulenc finally discovered phenothiazines that had antihistaminic properties. This led to the 1950 synthesis of neuroleptics.

Pharmacological action

The starting compound for numerous neuroleptics is phenothiazine. This refers to a tricyclic connection. Their middle ring has as a heterocycle a sulfur atom and a nitrogen atom. Phenothiazines have an affinity for the dopamine receptors. So they are able to block these. But other neurotransmitters such as norepinephrine, histamine and serotonin are inhibited by them.

The skeleton of the phenothiazines consists of three rings. Depending on the substitution of the backbone, a distinction is made between three phenothiazine groups. Thus, there are phenothiazines with alipathic series chain, piperidyl side chain and piperazinyl side chain. The alipathic phenothiazines have strong sedative effects, while they can cause side effects in the vegetative area.

The alipathic phenothiazines include promazine, levomepromazine, chlorpromazine, triflupromazine, promethazine, and profenamine. Piperidyl phenothiazines such as thioridazine, mesoridazine and periciazine have a moderately potent calming effect.

Piperazinyl phenothiazines, on the other hand, have only weak sedative and antihistaminic effects. But they develop a pronounced antiemetic and antipsychotic effect. Their representatives include perphenazine, fluphenazine, prochlorperazine and trifluoperazine.

Furthermore, phenothiazines can act locally anesthetizing, anti-adrenergic and ganglionic, giving them a broader spectrum than other neuroleptics.

The degradation of phenothiazines takes place in the liver. The pharmacological activity of the metabolites has not yet been clarified. The slow elimination of the drug from the body takes place via the kidneys.

Medical application & use

In medicine, the phenothiazines can be used in different fields. They serve as neuroleptics for the treatment of psychoses and influence the psyche of patients. They are particularly suitable for the treatment of schizophrenia, to combat hallucinations and delusions.

In addition, the phenothiazines can be administered as tranquilizers (sedatives). As anti-emetics, they fight dizziness and vomiting while treating allergic reactions as antihistamines.

A particularly well-proven phenothiazine is the low-potency promethazine. Thus, it has been successfully administered for decades against agitation and anxiety.

Risks & Side Effects

As dopamine antagonists, phenothiazines can cause numerous side effects, some of which are severe. These include extrapyramidal motor effects such as dystonia, early dyskinesia, tardive dyskinesia, motor unrest and Parkinson's symptoms such as tremors, rigidity and pathological immobility.

These undesirable effects are due to the blockade of the highly effective substances on the dopamine receptors. Phenothiazines of the chlorpromazine type also cause a disruption of the body's heat regulation. Other drugs of this type in turn trigger a long-QT syndrome, causing severe cardiac arrhythmia, which can take a fatal course.

Phenothiazines also have psychic side effects such as impulses to drive, impoverishment of the emotional life and restlessness in the realm of the possible. Some patients develop mental dependence on the drug.

In the case of organic side effects there is a risk that kidneys and liver will be affected. In addition, overdosing of phenothiazines is considered to be of health concern. This can cause discomfort such as blurred vision, trembling, low blood pressure, rapid heartbeat, drowsiness, impaired locomotor coordination, convulsions, psychomotor excitement and hallucinations. Some sufferers have even fallen into a coma. Tags: 

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